The making of a maggot: patterning the Drosophila embryonic epidermis.

Cell fates are instructed by signals emitted from specialized cell populations called organizers. The study of epidermal patterning in Drosophila is contributing novel insights concerning the establishment and action of such organizers. Juxtaposed rows of cells express either the wingless or hedgehog signaling molecules and thereby act as organizers of segment pattern. These signals mediate a mutually re-enforcing interaction between the two rows of cells to sustain organizer function. In a distinct and subsequent phase, wingless and hedgehog act to specify the fates of cells.

CD1 expression on antigen-presenting cells.

CD1 proteins present self and microbial glycolipids to CD 1-restricted T cells, or in the case of CD1d, to NKT cells. The CD1 family in humans consists of group I proteins CDla, CDlb, CDlc, and CDle and the group II protein CDld. Rodents express only CDld, but as CD1d is broadly expressed and traffics to all endosomal compartments, this single CD1 family member is thereby able to acquire antigens in many subcellular compartments. A complete understanding of the CD 1 family requires an appreciation of which cells express CD1 and how CD1 contributes to the unique function of each cell type. While group I CD 1 expression is limited to thymocytes and professional APCs, CD1d has a wider tissue distribution and can be found on many nonhematopoietic cells. The expression and regulation of CD1 are presented here with particular emphasis on the function of CD1 in thymocytes, B cells, monocytes and macrophages, dendritic cells (DCs), and intestinal epithelial cells (IECs). Altered expression of CD 1 in cancer, autoimmunity, and infectious disease is well documented, and the implication of CD 1 expression in these diseases is discussed.

Nodal-related signals establish mesendodermal fate and trunk neural identity in zebrafish.

The vertebrate body plan arises during gastrulation, when morphogenetic movements form the ectoderm, mesoderm, and endoderm. In zebrafish, mesoderm and endoderm derive from the marginal region of the late blastula, and cells located nearer the animal pole form the ectoderm [1]. Analysis in mouse, Xenopus, and zebrafish has demonstrated that Nodal-related proteins, a subclass of the TGF-beta superfamily, are essential for mesendoderm development [2], but previous mutational studies have not established whether Nodal-related signals control fate specification, morphogenetic movements, or survival of mesendodermal precursors. Here, we report that Nodal-related signals are required to allocate marginal cells to mesendodermal fates in the zebrafish embryo. In double mutants for the zebrafish nodal-related genes squint (sqt) and cyclops (cyc) [3] [4] [5], dorsal marginal cells adopt neural fates, whereas in wild-type embryos, cells at this position form endoderm and axial mesoderm. Involution movements characteristic of developing mesendoderm are also blocked in the absence of Nodal signaling. Because it has been proposed [6] that inhibition of Nodal-related signals promotes the development of anterior neural fates, we also examined anteroposterior organization of the neural tube in sqt;cyc mutants. Anterior trunk spinal cord is absent in sqt;cyc mutants, despite the presence of more anterior and posterior neural fates. These results demonstrate that nodal-related genes are required for the allocation of dorsal marginal cells to mesendodermal fates and for anteroposterior patterning of the neural tube.

Calcium and growth factor pathways of c-fos transcriptional activation require distinct upstream regulatory sequences.

Transcription of the c-fos proto-oncogene is rapidly induced in the rat pheochromocytoma PC12 cell line by a wide variety of stimuli, including polypeptide growth factors, phorbol esters, and calcium ion fluxes. We have mapped the upstream sequence requirements for this activation in PC12 cells by analysis of promoter deletion mutants in a transient expression assay. Two distinct pathways of c-fos induction are defined that differ in their requirement for cis-acting DNA sequences. Calcium activation of c-fos transcription is dependent on a DNA element located approximately 60 base pairs upstream of the transcription start site. This region is highly conserved between human, mouse, and chicken c-fos genes and contains a sequence that resembles the consensus for a cyclic AMP response element. The dyad symmetry element at position -300, which is necessary for serum responsiveness of c-fos, appears to be unimportant for calcium activation of the gene. The dyad symmetry element is, however, an essential cis-acting sequence for c-fos inducibility by nerve growth factor, epidermal growth factor, fibroblast growth factor, and the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate. Studies in vivo and in vitro with various mutants of the dyad symmetry element indicate that c-fos activation by polypeptide growth factors and 12-O-tetradecanoyl activation by polypeptide growth factors and 12-O-tetradecanoyl phorbol-13-acetate is mediated by a common transcription factor, and that this factor is identical to the previously described serum response factor. In vitro DNA-binding assays suggest that the quantity of serum response factor-binding activity remains unchanged during c-fos transcriptional activation.

Men who have sex with men who are born abroad and diagnosed with HIV in England and Wales: an epidemiological perspective.

Relatively little is known about the sexual health needs of men who have sex with men (MSM) born abroad who reside in the UK. We describe here the epidemiology of HIV among MSM born outside the UK and diagnosed with HIV in England and Wales. Reports of HIV diagnoses in England and Wales received at the Health Protection Agency Centre for Infections were analysed. Between 2000 and 2003, 6386 MSM were diagnosed with HIV in England and Wales. Country of birth was recorded for 3571 (56%). Of those with country of birth reported, 2598 (73%) were born in the UK and 973 (27%) abroad. Of those born abroad (973), 424 (44%) were born in Europe, 141 (15%) in Africa, 104 (11%) in South/Central America and the remainder in other regions. Where reported (949), 69% of MSM born abroad were White, 12% other/mixed, 9% Black Caribbean and 7% Black African. Probable country of infection was reported for 612 MSM born abroad: 52% were infected in the UK, 43% in their region of birth and 5% in another region. Men born abroad represent a significant proportion of HIV diagnoses among MSM in England and Wales. More than half probably acquired their HIV infection in the UK, strengthening the call for targeted HIV prevention and sexual health promotion among MSM who are not born in England and Wales.

New diagnoses of HTLV infection in England and Wales: 2002-2004.

Human T cell lymphotropic viruses (HTLV) are retroviruses transmitted through breastfeeding, sexual contact, blood transfusion and injecting drug use. HTLV is endemic in the Caribbean, and parts of Africa, Japan and South America, with isolated foci in other areas. Infection is life long. Fewer than 5% of those infected progress to one of the HTLV-related diseases, but these are debilitating and often fatal. In England and Wales, laboratory and clinical reports of new HTLV diagnoses are routinely collected, including infections identified by the blood service since the introduction of anti-HTLV testing in August 2002. Between 2002 and 2004, 273 individuals were diagnosed with HTLV: 102 (37%) were male and 169 female (sex was not reported for two). Median ages at diagnosis were 54 and 50 years respectively. Clinical reports were received for 78% (212/273) individuals. Where reported, 58% (116/199) of individuals were of black Caribbean ethnicity and 29% (57/199) white; 87% (128/147) were probably infected heterosexually or through mother-to-child transmission; 45% (66/146) were probably infected in the Caribbean and 40% (59/146) in the United Kingdom. An appreciable number of HTLV infections continue to be diagnosed within England and Wales, with increases in 2002-2003 because of anti-HTLV testing of blood donations. While most infections diagnosed are directly associated with the Caribbean, transmission of HTLV infection is occurring within England and Wales. Specialist care services for HTLV-infected individuals and their families have improved in recent years, but prevention remains limited.

New diagnoses of HTLV infection in England and Wales: 2002-2004.

Human T cell lymphotropic viruses (HTLV) are retroviruses transmitted through breastfeeding, sexual contact, blood transfusion and injecting drug use. HTLV is endemic in the Caribbean, and parts of Africa, Japan and South America, with isolated foci in other areas. Infection is life long. Fewer than 5% of those infected progress to one of the HTLV-related diseases, but these are debilitating and often fatal. In England and Wales, laboratory and clinical reports of new HTLV diagnoses are routinely collected, including infections identified by the blood service since the introduction of anti-HTLV testing in August 2002. Between 2002 and 2004, 273 individuals were diagnosed with HTLV: 102 (37%) were male and 169 female (sex was not reported for two). Median ages at diagnosis were 54 and 50 years respectively. Clinical reports were received for 78% (212/273) individuals. Where reported, 58% (116/199) of individuals were of black Caribbean ethnicity and 29% (57/199) white; 87% (128/147) were probably infected heterosexually or through mother-to-child transmission; 45% (66/146) were probably infected in the Caribbean and 40% (59/146) in the United Kingdom. An appreciable number of HTLV infections continue to be diagnosed within England and Wales, with increases in 2002-2003 because of anti-HTLV testing of blood donations. While most infections diagnosed are directly associated with the Caribbean, transmission of HTLV infection is occurring within England and Wales. Specialist care services for HTLV-infected individuals and their families have improved in recent years, but prevention remains limited.

Psychological sequelae to carbon monoxide intoxication in the child.

Twenty children from 25 months to 15 years old at the time of carbon monoxide intoxication have been studied in a short-term follow-up, and 14 children in a long-term follow-up, as far as their psychological and cognitive faculties are concerned. The quality of recovery is a function of the severeness of the intoxication, but the intellectual level of the children, and primarily their age at the time of the intoxication, also play a major role.

HIV in gay and bisexual men in the United Kingdom: 25 years of public health surveillance.

It is more than 25 years since the first case of AIDS was reported in the United Kingdom. In December 1981 a gay man was referred to a London hospital with opportunistic infections indicative of immunosuppression. National surveillance began the following year, in September 1982, with the notification of deaths and clinical reports of AIDS and Kaposi's sarcoma plus laboratory reports of opportunistic infections. Since then epidemiological surveillance systems have evolved, adapting to, and taking advantage of advances in treatments and laboratory techniques. The introduction of the HIV antibody test in 1984 led to the reporting of HIV-positive tests by laboratories and the establishment of an unlinked anonymous survey in 1990 measuring undiagnosed HIV infection among gay men attending sexual health clinics. The widespread use of highly active antiretroviral therapies (HAART) since 1996 has averted many deaths among HIV-positive gay men and has also resulted in a large reduction in AIDS cases. This led to a need for an enumeration of gay men with HIV accessing NHS treatment and care services (1995 onwards), more clinical information on HIV diagnoses for epidemiological surveillance (2000 onwards) and the routine monitoring of drug resistance (2001 onwards). Twenty-five years after the first case of AIDS was reported, gay and bisexual men remain the group at greatest risk of acquiring HIV in the United Kingdom. Latest estimates suggest that in 2004, 26 500 gay and bisexual men were living with HIV in the United Kingdom, a quarter of whom were undiagnosed. In this review, we examine how national surveillance systems have evolved over the past 25 years in response to the changing epidemiology of HIV/AIDS among gay and bisexual men in the United Kingdom as well as advances in laboratory techniques and medical treatments. We also reflect on how they will need to continue evolving to effectively inform health policy in the future.

Late diagnosis of HIV infection among individuals with low, unrecognised or unacknowledged risks in England, Wales and Northern Ireland.

A small number of UK nationals who have a low, unrecognised or unacknowledged risk for HIV present late in the course of HIV infection; often after frequent attendances to primary care physicians. Information from in-depth interviews with individuals diagnosed with HIV in England, Wales and Northern Ireland (EW&NI) was analysed. Those diagnosed because of HIV-related symptoms (late diagnoses) were compared with those diagnosed for other reasons. Of the 286 individuals interviewed, 157 (55%) had HIV-related symptoms at the time of diagnosis, and 129 were tested for other reasons. A greater proportion of those diagnosed late were male and older. Of the 157 late diagnoses, 77 were considered to have acquired HIV heterosexually in the UK, 19 heterosexually abroad, 16 through 'high-risk' behaviours, 15 heterosexually by a 'high-risk' partner, four through blood transfusion and the remainder through an unusual or unknown route. A significantly higher proportion of those diagnosed late had had a long-standing relationship. None had been informed by a current or ex-partner of their HIV status. Primary care physicians should consider HIV as a possibility when patients without an apparent risk for HIV-infection present with symptoms indicative of possible immune suppression. Sensitive partner notification practices that enable a greater number of individuals to inform their partners should be explored.

Factors associated with heterosexual transmission of HIV to individuals without a major risk within England, Wales, and Northern Ireland: a comparison with national probability surveys.

OBJECTIVE: To compare the prevalence of HIV risk behaviours reported by heterosexuals without major risks for HIV acquisition diagnosed with HIV in England, Wales, and Northern Ireland, with those of the heterosexual general population. METHODS: Demographic and sexual behaviour data for heterosexuals (without major risks for HIV) aged 16-44 from the British National Surveys of Sexual Attitudes and Lifestyles in 1990 and 2000 were compared to 139 HIV infected individuals without major risks for HIV aged 16+ at diagnosis, interviewed between December 1987 and March 2003. Comparisons were made overall and separately for the early and late 1990s. RESULTS: HIV infected heterosexual men without major risks were significantly more likely to report first heterosexual intercourse before age 16 (adjusted odds ratio (AOR): 2.75; 95% confidence interval (CI),1.65 to 4.57), while both HIV infected heterosexual men and women reported greater partner numbers (AOR: men 2.44; CI, 1.4 to 4.05; AOR women 2.17; CI, 1.28 to 3.66) and never using condoms (AOR: men 7.97; CI,4.78 to 13.3; AOR women 3.95; CI, 2.30 to 6.80) than the heterosexual general population. There is evidence to suggest that the two groups were more similar in their reporting of partner numbers in the late 1990s relative to the early 1990s. CONCLUSION: Heterosexual HIV infected individuals without major risks for HIV acquisition in England, Wales, and Northern Ireland are significantly more likely to report high risk sexual behaviours relative to the British heterosexual general population. However, these differences may have decreased over time, at least for the number of partners. Effective sexual health promotion, including the continued promotion of condom use, would impact on the rising rates of STI diagnoses and also prevent HIV transmission among the heterosexual general population.

Diagnoses of HIV-1 and HIV-2 in England, Wales, and Northern Ireland associated with west Africa.

OBJECTIVES: To describe HIV diagnoses, including those of HIV-2 infection, made in England, Wales, and Northern Ireland (E,W&NI) among those probably infected in west Africa, and to consider whether there is evidence for ongoing heterosexual transmission within the United Kingdom. METHODS: Reports of new HIV diagnoses received at the Communicable Disease Surveillance Centre were analysed. Individuals probably infected in west Africa and those infected through heterosexual intercourse within the United Kingdom by a heterosexual partner infected in west Africa were included. RESULTS: Between 1985 and 2003 inclusive, 1324 individuals diagnosed and reported with HIV had probably been infected in west Africa, with 222 diagnoses made in 2003. 917 (69%) were HIV-1 infected and 52 (6%) HIV-2 or HIV-1/HIV-2 co-infected. For 355 (27%) the HIV type was not reported. The proportion of HIV-2 and HIV-1/HIV-2 infections varied by country of infection (p<0.001): ranging from the Gambia (11.7%-15.2%) to Nigeria (0.7%-1.0%). A further 130 individuals were probably infected through heterosexual intercourse within the United Kingdom by a heterosexual partner infected in west Africa. 89 (68%) were HIV-1 infected and three (2%) HIV-2 infected or HIV-1/HIV-2 co-infected. For 38 (29%) HIV type was not reported. CONCLUSION: The number of people infected with HIV in west Africa and diagnosed in E,W&NI has increased in recent years, and there is evidence of heterosexual transmission within the United Kingdom from people infected in west Africa. While numbers of HIV-2 diagnoses remain relatively low, an appreciable proportion of people infected in some west African countries and diagnosed in the United Kingdom may be HIV-2 positive, with implications for prognosis and treatment.

Epidemiology of HIV among black and minority ethnic men who have sex with men in England and Wales.

OBJECTIVES: To examine the epidemiology of HIV among black and minority ethnic (BME) men who have sex with men (MSM) in England and Wales (E&W). METHODS: Ethnicity data from two national HIV/AIDS surveillance systems were reviewed (1997-2002 inclusive), providing information on new HIV diagnoses and those accessing NHS HIV treatment and care services. In addition, undiagnosed HIV prevalence among MSM attending 14 genitourinary medicine (GUM) clinics participating in the Unlinked Anonymous Prevalence Monitoring Programme and having routine syphilis serology was examined by world region of birth. RESULTS: Between 1997 and 2002, 1040 BME MSM were newly diagnosed with HIV in E&W, representing 12% of all new diagnoses reported among MSM. Of the 1040 BME MSM, 27% were black Caribbean, 12% black African, 10% black other, 8% Indian/Pakistani/Bangladeshi, and 44% other/mixed. Where reported (n = 395), 58% of BME MSM were probably infected in the United Kingdom. An estimated 7.4% (approximate 95% CI: 4.4% to 12.5%) of BME MSM aged 16-44 in E&W were living with diagnosed HIV in 2002 compared with 3.2% (approximate 95% CI: 2.6% to 3.9%) of white MSM (p<0.001). Of Caribbean born MSM attending GUM clinics between 1997 and 2002, the proportion with undiagnosed HIV infection was 15.8% (95% CI: 11.7% to 20.8%), while among MSM born in other regions it remained below 6.0%. CONCLUSIONS: Between 1997-2002, BME MSM accounted for just over one in 10 new HIV diagnoses among MSM in E & W; more than half probably acquired their infection in the United Kingdom. In 2002, the proportion of BME MSM living with diagnosed HIV in E&W was significantly higher than white MSM. Undiagnosed HIV prevalence in Caribbean born MSM was high. These data confirm the need to remain alert to the sexual health needs and evolving epidemiology of HIV among BME MSM in E&W.

Drosophila wingless generates cell type diversity among engrailed expressing cells.

During embryogenesis, body pattern is established in a stepwise process. After specification of the body axis, the embryo is subdivided into smaller units. Within these units, a diverse array of cell types is then generated. The subdivisions of the Drosophila embryo, called parasegments, are defined by the interface between cells expressing the homeoprotein Engrailed and cells expressing the secreted protein Wingless. We have examined the generation of cell-type diversity within parasegments by focusing on the choice of cell fate made by the engrailed (en)-expressing cells. These cells differentiate as one of two alternative cell types. We report here that this choice is mediated by wingless (wg), in a function distinct from its early role maintaining en expression. Thus, en cells exhibit different responses to the wg signal at different developmental stages. Early wg input stabilizes the subdivision of the body axis by maintaining en expression, whereas later input generates cell-type diversity.

Overcounting of black Africans in the UK: the problem of undetected record duplication.

Difficulties in recording unfamiliar African names, leading to inconsistent reporting of 'surname' code of the same individual, has raised concern that there is overcounting of newly diagnosed HIV-positive black Africans in the UK. Date of birth was used as a proxy indicator for duplication of entries of black Africans in the national HIV/AIDS patient database. Significantly more black Africans (59%) than whites (56%) share the same date of birth (p = 0.0023), and among black Africans certain birthdays occur at a very high frequency. Those born in Africa may not know their exact date of birth and so may be choosing, or have chosen for them, memorable or auspicious dates instead. After removal of individuals with birthdays consisting of the same number day and month, the evidence of disproportionate duplication of black Africans' dates of birth was weaker (p = 0.0129). Although this investigation provided evidence of selective failure to detect duplicated reports of the same individual among reports of HIV-positive black Africans, in practical terms, the relatively small proportion (2.4%) of remaining excess duplicates is equivalent to 141 black African individuals on the database, and would not impact on the overall picture of the HIV epidemic in the UK.

bozozok and squint act in parallel to specify dorsal mesoderm and anterior neuroectoderm in zebrafish.

In vertebrate embryos, maternal (beta)-catenin protein activates the expression of zygotic genes that establish the dorsal axial structures. Among the zygotically acting genes with key roles in the specification of dorsal axial structures are the homeobox gene bozozok (boz) and the nodal-related (TGF-(beta) family) gene squint (sqt). Both genes are expressed in the dorsal yolk syncytial layer, a source of dorsal mesoderm inducing signals, and mutational analysis has indicated that boz and sqt are required for dorsal mesoderm development. Here we examine the regulatory interactions among boz, sqt and a second nodal-related gene, cyclops (cyc). Three lines of evidence indicate that boz and sqt act in parallel to specify dorsal mesoderm and anterior neuroectoderm. First, boz requires sqt function to induce high levels of ectopic dorsal mesoderm, consistent with sqt acting either downstream or in parallel to boz. Second, sqt mRNA is expressed in blastula stage boz mutants, indicating that boz is not essential for activation of sqt transcription, and conversely, boz mRNA is expressed in blastula stage sqt mutants. Third, boz;sqt double mutants have a much more severe phenotype than boz and sqt single mutants. Double mutants consistently lack the anterior neural tube and axial mesoderm, and ventral fates are markedly expanded. Expression of chordin and noggin1 is greatly reduced in boz;sqt mutants, indicating that the boz and sqt pathways have overlapping roles in activating secreted BMP antagonists. In striking contrast to boz;sqt double mutants, anterior neural fates are specified in boz;sqt;cyc triple mutants. This indicates that cyc represses anterior neural development, and that boz and sqt counteract this repressive function. Our results support a model in which boz and sqt act in parallel to induce dorsalizing BMP-antagonists and to counteract the repressive function of cyc in neural patterning.

Recent trends in diagnoses of HIV and other sexually transmitted infections in England and Wales among men who have sex with men.

OBJECTIVES: To examine trends in rates of diagnoses of HIV and other sexually transmitted infections (STIs) in men who have sex with men (MSM) in England and Wales between 1997 and 2002. METHODS: Estimates of the MSM population living in England and Wales, London and the rest of England and Wales were applied to surveillance data, providing rates of diagnoses of HIV and STIs and age group specific rates for HIV and uncomplicated gonorrhoea. RESULTS: Between 1997 and 2002, rates of diagnoses of HIV and acute STIs in MSM increased substantially. Rates in London were higher than elsewhere. Rises in acute STIs were similar throughout England and Wales, except for uncomplicated gonorrhoea and infectious syphilis, with greater increases outside London. Rates of gonorrhoea diagnoses doubled between 1999 and 2001 (661/100,000, 1271/100,000, p<0.001) in England and Wales followed by a slight decline to 1210/100,000 (p=0.03) in 2002-primarily the result of a decline in diagnoses among men aged 25-34 (1340/100,000, 1128/100,000, p<0.001) and 35-44 (924/100,000, 863/100,000, p=0.03) in London. HIV was the third most common STI diagnosed in MSM in England and Wales and the second in London, with the highest rate (1286/100,000) found among men aged 35-44 in London in 2002. CONCLUSIONS: Rates of diagnosis of HIV and other STIs have increased substantially among MSM in England and Wales. Increases show heterogeneity by infection, geography, and age over time. Rates in London were twice those seen elsewhere, with greatest changes over time. The observed changes reflect concomitant increases in high risk behaviour documented in behavioural surveillance survey programmes.

HTLV infection in England and Wales in 2002--results from an enhanced national surveillance system.

Human T-cell lymphotropic virus (HTLV) is a retrovirus transmitted through breastfeeding, sexual contact, blood transfusion and injecting drug use. HTLV is endemic in the Caribbean and parts of Africa, Japan and South America, with isolated foci in other areas. Infection is life-long. Less than 5% of those infected progress to one of the HTLV-related diseases, but these are debilitating and often fatal. Laboratory reports of new HTLV diagnoses are followed up through clinicians to establish information such as probable country of infection, country of birth, clinical details and reason for test. Clinician reports are also received for HTLV-infected blood donors identified by the National Blood Service. Seventy-seven individuals newly diagnosed with HTLV infection in 2002 were reported to the Communicable Disease Surveillance Centre (CDSC) by June 2003. Thirty-three (43%) were male, and 44 (57%) female, with median ages at diagnosis of 58.5 and 50.1 years respectively. Seventy-three (95%) individuals were HTLV-I positive and three HTLV-II positive, with one remaining untyped. For 52 of the 77 infections, clinician reports were received. Where ethnicity was reported (48), 30 (63%) were Black Caribbean, 12 (25%) White, and the remainder (6) of other ethnicities. Probable route of infection was reported for 31 individuals: nine (29%) were probably infected heterosexually, seven (23%) through mother-to-child transmission, 12 (40%) through either route, two through blood transfusion, and one through injecting drug use (HTLV-II positive). Where probable country of infection was reported (31), 14 (45%) were probably infected in the UK, 13 (42%) in the Caribbean, and four elsewhere. Where reported (50), reason for test was: symptoms for 19 (38%) individuals, blood donation for 21 (42%), and the remainder for other reasons. Numbers of new HTLV diagnoses were relatively high in 2002, and the characteristics of patients and clinical presentations differed from previous years, mainly due to the introduction of blood donor testing for anti-HTLV. Beyond 2004, the number of HTLV-infected individuals detected through blood donation is expected to decline. While numbers of individuals affected are small compared to many other diseases, the infection is chronic and untreatable, and it is important that adequate standards of diagnosis, prevention, care and support are provided, and surveillance maintained.